It is the purpose of this study to characterize and quantitate the modifications of the in vitro cellular heat sensitivity by step-down heating, thermotolerance, low pH and nutrient deprivation as a function of temperature. The second part of the study is aimed at documenting the interaction of these variables on the cellular heat response. The studies will be carried out on two cultured cell lines which differ in their response to heating at low pH and their sensitivity to temperatures below 43 degrees. The four conditions for modulating the cellular heat sensitivity most likely operate in vivo and therefore are relevant to applications of hyperthermia in cancer therapy. A manipulation of these parameters for increased therapeutic ratios must be based on an understanding of the temperature dependence of the modulating conditions and their interactions. In addition, the documentation of how these variables affect the thermal response per se and how they interact with each other should provide a system for establishing correlations with molecular heat-induced lesions which may lead to the identification of "critical heat targets" and their repair systems.